Parkinson's disease is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons of the substantia nigra pars compacta (SN). The etiology is largely unknown and there is no cure available. Although current pharmacotherapies are modestly successful in ameliorating motor deficits, late complications of the therapies limit their long-term utility. The paucity of adult CNS plasticity is a further limit to structural repair of the striatonigral system. However, there is recent evidence that some areas of the adult brain retain the ability of continued generation of new cells including neurons and that this process contributes to repair following neuronal injury. Our results show that continued cell generation occurs in the adult SN. In addition, we have evidence that the resident proliferating cells in the adult SN have the potential to give rise to neurons. We propose that continued cell generation in the adult SN can be exploited for future endogenous dopaminergic cell replacement therapies in Parkinson's disease. In this grant we will examine cell genesis in the adult SN under three conditions in vivo: cell genesis in the intact adult SN; cell genesis in the adult SN in behavioral paradigms that stimulate neurogenesis in other CNS regions; cell genesis in the SN in an experimental model for Parkinson's disease. These in vivo studies will be complemented by a set of experiments in which we will: investigate the characteristics of proliferating cells derived from the adult SN in vitro; define conditions which will enhance dopaminergic cell generation from these cells. The suggested experiments will provide the groundwork for possible future strategies in which we will try to manipulate cell genesis in the adult SN in order to restore the function of the injured adult SN.